Shock wave lithotripsy (SWL) is a very effective non-invasive treatment modality for the removal of upper urinary tract stones. However, SWL causes trauma to the kidney that can lead to serious long-term complications in some individuals (e.g. new onset hypertension in the elderly; delayed kidney growth in the very young). While the efficacy of SWL is not in question, the severity of complications raises concern for the long-term safety of SWL. Little is known about the cellular level mechanisms involved in SWL injury and the tissue level changes that lead to chronic alterations in kidney structure and function. Likewise, it is not known how lithotripter shock waves (Sw's) break kidney stones. Thus, the principal objectives of the proposed research are to determine: 1) the physical mechanisms of stone comminution and tissue damage in SWL; 2) the cellular mechanisms of SW- physical mechanisms of stone comminution and tissue damage in SWL; 2) the cellular mechanisms of SW-induced tissue injury; 3) the progression of tissue level changes initiated changes initiated by SW trauma that lead to scar formation; and 4) the factors (renal and extrarenal) that place patients at increased risk of injury. Our research effort in this Program Project Grant is organized around four Projects and two Cores. Project 1 (Indiana University & Methodist Hospital of Indiana) will use a whole animal model (pig) to determine how SW treatment causes renal hemorrhage and vasoconstriction, to define the tissue response that leads to scar formation and to assess for potential risk factors that may enhance SWL injury. Project 2 (Indians University) will use cultured cells and a variety of in vitro models that determine the cellular mechanisms involved in tissue damage and how acoustic cavitation and shear cause cell injury. Project 3 (University of Washington) will use sophisticated methods of cavitation to determine the role of cavitation in stone comminution and tissue injury. Project 4 (California Institute of Technology) will examine the role of shock waves shear as a fundamental mechanism that contributes to tissue failure and stone comminution. The overall goal of this research is to determine the physical mechanisms of stone comminution and the cause and consequences of SW-induced renal injury so that strategies can be devised to minimized or eliminate adverse effect while improving the efficacy of SWL.